Liquid pharmaceutical compositions comprising thyroid hormones

ABSTRACT

There is disclosed a liquid pharmaceutical composition comprising a therapeutic agent which comprises: one or more thyroid hormone or hormones; from about 40% to about 96% ethanol by volume; a pH adjusting agent so that the measured pH of the composition is from about 9 to about 12; and from about 4% to about 50% water by volume; which has utility in the treatment of disorders associated with an impairment of the thyroid hormone function in animals including human beings. The liquid composition may be delivered by a metered dosage delivery system such as an aerosol or pump-action spray.

This application is a 371 of PCT/EP95/00323 filed on Jan. 30, 1995.

This invention relates to novel pharmaceutical compositions comprisingat least one thyroid hormone and their derivatives, and to their use inthe treatment of disorders associated with impairment of the thyroidhormone functions in animals including human beings.

Many patients, particularly the elderly or small children may havedifficulty swallowing traditional oral dosage forms. For these patientsliquid dosage forms may result in increased patient compliance. Liquiddosage forms may also have the advantage of more reproduciblebioavailability over solid dosage forms. However, liquid oral dosageforms (such as solutions, syrups and suspensions) comprising thyroidhormones are difficult to dose accurately due to the small (microgram)quantities of active ingredient. For these reasons products in liquidoral dosage form comprising thyroid hormones are not currentlyavailable. Therefore it is an object of the present invention to providea liquid dosage form and delivery system for thyroid hormone which hasimproved patient compliance over traditional solid oral dosage forms,which can accurately deliver small doses of thyroid hormone, and whichhas a suitably long shelf life.

Thyroid hormones comprise one or more of the following:

L-3,5,3′, 5′-tetraiodothyronine (levothyroxine or LT4);

L-3,5,3′-triiodothyronine (liothyronine or LT3);

L-3,3′, 5,-triiodothyronine (LrT3);

L-3,5-diiodothyronine (LT2); or any mixtures thereof.

As used herein the term thyroid hormone should be understood to includepharmaceutically acceptable salts thereof, preferably sodium salts.

Thyroid hormones as described herein are useful in the treatment ofdisorders associated with improvement of the thyroid hormone function inanimals including human beings for example, myxedema, cretinism orobesity. Thyroid hormones can be prepared synthetically as thebiologically active 1-enantiomer or can be isolated directly from thethyroid gland of animals.

Solutions are a highly useful means of administering accurately metereddoses of drug substances. However, thyroid hormones are known to beunstable in solution and are not normally sufficiently soluble in waterfor the intended purpose. Surprisingly, it has been discovered that anethanolic aqueous solution can form the basis of a stable solutioncomprising thyroid hormones suitable for use in liquid formulationswhich can be delivered in metered doses.

Therefore the present invention provides a liquid pharmaceuticalcomposition comprising a therapeutic agent which comprises at least onethyroid hormone; from about 40% to about 96% ethanol by volume; a pHadjusting agent so that the measured pH of the composition is from about9 to about 12; and from about 4% to about 50% water by volume.

‘By volume’ throughout the specification and claims indicates apercentage is the volume of a liquid ingredient per total volume of theliquid composition. ‘By mass’ indicates a percentage is the mass of aningredient per total mass of the composition.

Thyroid hormones may exist as one or more olymorphic forms (for exampleone or more crystalline forms, amorphous forms, phases, solid solutionsand/or mixtures thereof), and the therapeutic agent may include andpharmaceutically acceptable polymorphic forms of thyroid hormones and/ormixtures thereof.

Thyroid hormones may also exist in the forms of solvates (for examplehydrates) and the therapeutic agent may include each solvate of thethyroid hormones and/or mixtures thereof.

Preferably the thyroid hormone is present in the compositions in anamount per unit dose from about 0.1 μg to about 10,000 μg, morepreferably from about 1 μg to about 1000 μg, most preferably if thethyroid. hormone is LT₄ from about 25 μg to about 300 μg. It will bereadily appreciated that the doses of thyroid hormone will varyaccording to which thyroid hormone or derivative is used and willtherefore be adjusted accordingly.

Preferably the volume of the composition per unit dose is about 0.1 μlto about 10,000 μl, more preferably from about 1 μl to about 1,000 μl,most preferably if the thyroid hormone is LT₄ from about 10 μl to about600 μl.

The concentration of thyroid hormone in liquid compositions of theinvention will vary according to the unit dose or volume desired andwhich thyroid hormone derivative is used. However, typically if thethyroid hormone is LT₄ the concentration will be from about 0.1 mg ml⁻¹to about 1.0 mg ml⁻¹.

Preferably the ethanol is present in an amount from about 50% to about80%, more preferably from about 60% to about 75%, by volume of thecomposition.

Preferably the composition further comprises from a trace amount toabout 5% by mass of a pharmaceutically acceptable sequestrating agentwhich may be an ethylene diamine tetra-acetate salt (eg, sodium salt).

Preferably the composition additionally comprises from a trace amount toabout 5% by mass of an pharmaceutically acceptable antioxidant which maybe a metabisulphite or sulphite salt (eg,a sodium salt).

Preferably the pH adjusting agent is sodium hydroxide and the measuredpH of the formulation is from about 9 to about 11, more preferably about10. It will be readily appreciated by persons skilled in the art that apH measured in a non-aqueous solvent by a suitable means (for example apH meter) is not to be considered to relate directly to hydrogen ionconcentration but is to be used for comparative purposes only.

The liquid composition of the present invention may further comprise oneor more of the following pharmaceutically acceptable optionalingredients:

colouring agents, for example conventional pharmaceutically acceptabledyes;

orally acceptable preservatives, for example benzyl alcohol, sodiumhypochlorite, phenoxy ethanol and/or propylene glycol;

sweetening agents for example glycerin, sucrose, sorbitol, sodiumsaccharin and/or aspartame;

flavouring agents, for example sodium citrate and/or citric acid; and

thickening agents, for example povidone and/or hydroxypropylmethylcellulose.

These optional ingredients may be present in an amount from a traceamount to about 40% by mass of the composition, preferably (if theoptional ingredient is other than glycerin) from a trace amount to about10% by mass.

The formulation of the present invention is suitable for use in ametered dosage delivery system such as a pump-action spray or apressurised aerosol can, in which the propellent is preferably free ofoxygen.

Therefore a further aspect of the invention provides a metered dosagedelivery system which comprises a liquid composition as describedherein.

A further aspect of the present invention provides use of a thyroidhormone in the preparation of the pharmaceutical compositions describedherein for the treatment of disorders associated with an impairment ofthe thyroid hormone function in animals including human beings.

A still further aspect of the present invention provides a method oftreating disorders associated with an impairment of the thyroid hormonefunction in animals including human beings, which comprisesadministering to a patient in need thereof a therapeutically and/orprophylactically effective amount of the pharmaceutical compositionsdescribed herein.

Whilst the precise amount of the therapeutic agent administered in thetreatment described outlined above will depend on a number of factors,for example the severity of the condition, the age and past medicalhistory of the patient, and always lies within the sound discretion ofthe administering medical practioner or veterinary a suitable daily doseof a thyroid hormone for administration to animals, preferably humanbeings, may generally be from about 0.1 μg to about 10,000 μg,preferably from about 1 μg to about 1,000 μg, more preferably if thethyroid hormone is LT₄ from about 25 μg to about 300 μg, given in asingle dose or in divided doses at one or more times during the day.

Liquid compositions of the present invention provide a versatile meansin which to administer a unit dose of the therapeutic agent. For examplewhen the therapeutic agent is LT₄, the liquid dosage form may comprise aspray or aerosol comprising a solution having a concentration of LT₄ of1 mg ml⁻¹. Preferably the spray delivers a volume of solution per unitdose of from about 25 μl to about 300 μl (equivalent to a dose of fromabout 25 μg to about 300 μg). If the spray comprises a solution having aconcentration of LT₄ of 0.5 mg ml⁻¹ then preferably the spray delivers avolume of solution per unit dose of from about 50 μl to 600 μl(equivalent to a dose of from about 25 μg to about 300 μg of LT₄).

Pharmaceutical compositions of the present invention may be used inadjunctive therapy with one or more other compounds having activity inthe treatment of disorders associated with an impairment of the thyroidhormone function in animals including human beings. It will beappreciated that the term treatment as used herein includes prophylacticuse of the pharmaceutical compositions of the present invention, forexample to protect against conditions such as hypothyroidism, in animalsincluding human beings.

The invention will now be illustrated by the following non-limitingexamples. Throughout the examples % m/v indicates the percentage in theamount of ingredient by mass (g) per volume of the composition (ml) and% v/v indicates the percentage in the amount of ingredient by volume.

EXAMPLE 1

Ingredient % m/v Levothyroxine sodium (LT₄) 0.1 EDTA (Sequestrine NA4)0.05 Sodium metabisulphite 0.05 Sodium saccharin 0.10 Ethanol 70 (% v/v)Purified water to . . . 100

The above ingredients were mixed together to form an ethanolic solutionwhich had a pH, measured with a pH meter, of 9.3. The solution wasfiltered and sealed in ampoules, the headspace being air.

The stability of the therapeutic agent (LT₄) in this formulation wastested with the formulation held at various temperatures over 6 months.The results are tabulated below, as a fraction of LT₄ remaining. A dashindicates that no data are available for the amount of LT₄ present at aparticular temperature after a particular duration.

Duration Temp After 2 1 2 3 6 ° C. Initially weeks month months monthsmonths 4 0.97 — — 0.99 1.00 1.09 25 0.97 1.01 1.00 0.99 1.00 1.07 300.97 — — 0.99 — 1.07 40 0.97 — — — 0.97 1.00 50 0.97 1.03 0.94 — 0.880.81

EXAMPLES 2 TO 3

Ingredient % m/v Levothyroxine sodium (LT₄) 0.1 EDTA (Sequestrene NA4)0.05 Sodium sulphite 0.05 Glycerin 30.0 (% v/v) Ethanol 40.0 (% v/v)Purified water to . . . 100

The above ingredients were mixed to form a solution as in Example 1,which had a pH, measured with a pH meter, of 9.3. The stability resultsover 3 months for this solution filled into ampoules having either anair (Example 2) or nitrogen (Example 3) headspace are given in thefollowing table, as a fraction of LT₄ remaining.

Duration Temp 1 2 3 ° C. Initially month months months Example 2 -Ampoule (air) 4 0.97 0.99 0.99 0.97 25 0.97 0.98 0.98 0.95 40 0.97 0.990.95 0.80 50 0.97 0.97 0.83 0.68 Example 3 - Ampoule (nitrogen) 4 0.980.99 1.00 0.97 25 0.98 0.99 0.99 0.97 40 0.98 0.98 0.98 0.95 50 0.980.99 0.96 0.93

EXAMPLES 4 TO 6

Ingredient % m/v Levothyroxine sodium 0.1 EDTA (Sequestrene NA4) 0.05Sodium sulphite 0.05 Ethanol 70 (% v/v) Purified water to . . . 100

The above ingredients were mixed to form a solution as in Example 1,which had a pH, measured with a pH meter, of 10.1. The stability resultsare tabulated below in a similar manner to Examples 1 to 3 above for asolution filled into ampoules and having an air (Example 4) or anitrogen (Example 5) headspace. Stability results for a solutionprepared as above (with a measured pH of 10.0) which was filled into apump pack (Example 6) is also given in the following table. A ashindicates no data are available.

Duration Temp 1 2 3 6 ° C. Initially month months months months Example4 (ampoule - air) 4 1.01 0.99 1.0 0.99 0.98 25 1.01 1.00 0.95 0.99 0.9940 1.01 0.99 0.99 0.97 0.94 50 1.01 0.96 0.95 0.89 0.84 Example 5(Ampoule - nitrogen) 4 1.01 1.04 1.01 1.01 1.00 25 1.01 1.00 1.01 0.991.00 40 1.01 1.00 1.01 0.99 1.00 50 1.01 0.99 0.99 0.96 0.95 Example 5(Pump pack) 4 1.02 1.03 — 1.03 — 25 1.02 1.04 — 1.04 — 40 1.02 1.01 —1.05 — 50 1.02 1.00 — 0.99 —

EXAMPLES 7 TO 9

Ingredient % m/v Levothyroxine sodium 0.1 EDTA (Sequestrine NA4) 0.05Sodium sulphite 0.1 Ethanol 70 (% v/v) Purified water to . . . 100

The above ingredients were mixed as in Example 1 to produce a solutionwith a measured pH of 10.3, which was then stored as described inExamples 4 to 6. The stability results are 5 as follows. A dashindicates no data are available.

Duration Temp 1 2 3 6 ° C. Initially month months months months Example7 (Ampoule - air) 4 1.00 0.99 1.01 1.01 1.00 25 1.00 0.99 1.00 0.99 0.9840 1.00 0.98 0.99 0.96 0.97 50 1.00 0.96  0.965 0.91 0.86 Example 8(Ampoule - nitrogen) 4 1.01 0.99 1.01 1.00 1.01 25 1.01 0.99 1.01 1.001.00 40 1.01 0.99 1.00 1.00 1.01 50 1.01 0.99 1.01 0.99 0.97 Example 9(Pump pack) 4 1.03 1.02 — 1.02 — 25 1.03 1.02 — 1.03 — 40 1.03 1.03 —1.04 — 50 1.03 1.01 — 0.99 —

EXAMPLE 10 TO 12

Ingredient % m/v Levothyroxine sodium 0.1 EDTA (Sequestrene NA4) 0.05Sodium sulphite 0.1 Sodium saccharin 0.1 Ethanol 70 (% v/v) Purifiedwater to . . . 100

The above ingredients were mixed as in Example 1 to produced a solutionwith a measured pH of 10.2 and 10.3, which was then stored as describedin Examples 4 to 6. The stablity results are as follows. A dashindicates no data are available.

Duration Temp 1 2 3 6 ° C. Initially month months months months Example10 (Ampoule - air) 4 0.95 1.04 0.95 0.95 0.97 25 0.95 1.04 0.96 0.920.94 40 0.95 1.03 0.95 0.90 0.93 50 0.95 1.00 0.90 0.83 0.81 Example 11(Ampoule - nitrogen) 4 0.96 1.05 0.96 0.97 0.97 25 0.96 1.06 0.99 0.930.95 40 0.96 1.06 0.97 0.93 0.98 50 0.96 1.06 0.97 0.91 0.92 Example 12(Pump pack) 4 0.99 1.04 — 0.99 — 25 0.99 1.03 — 1.00 — 40 0.99 1.05 —0.99 — 50 0.99 1.02 — 0.95 —

What is claimed is:
 1. A stable liquid oral dosage pharmaceuticalcomposition, said composition comprising at least one thyroid hormoneselected from the group consisting of L-3,5,3′,5′-tetraiodothyronine(levothyroxine or LT4), L-3,5,3′-triiodothyronine (liothyronine or LT3),L-3,3′,5′-triiodothyronine (LrT3), L-3,5-diiodothyrone (LT2),pharmaceutically acceptable salts thereof, and mixtures thereof; fromabout 40% to about 96% of ethanol by volume; a pH adjusting agent sothat the measured pH of the composition is from about 9 to about 12; andfrom about 4% to about 50% water by volume.
 2. A composition as definedin claim 1, in which the ethanol is present in an amount from about 50%to about 80% by volume of the composition.
 3. A composition as definedin claim 1, which further comprises from a trace amount to about 5% bymass of the composition of a pharmaceutically acceptable sequestratingagent.
 4. A composition as defined in claim 1, which further comprisesfrom a trace amount to about 5% by mass of the composition of apharmaceutically acceptable anti-oxidant.
 5. A method of treating adisorder associated with an impairment of the thyroid hormone functionin a mammal, which method comprises administration to a mammal in needof such treatment a therapeutically effective amount of the stableliquid oral dosage pharmaceutical composition defined in claim
 1. 6. Amethod of preparing a stable oral liquid dosage pharmaceuticalcomposition as defined claim 1, which method comprises combining thethyroid hormone with from about 40% to about 96% of ethanol by volume;and from about 4% to about 50% water by volume; and then adjusting thepH of the resulting solution to a pH of from about 9 to about
 12. 7. Amethod as defined in claim 6, in which the ethanol is added to thecomposition in an amount from about 50% to about 80% by volume of thecomposition.
 8. A method as defined in claim 7, which further comprisesadding to the composition from a trace amount to about 5% by mass of thecomposition of a pharmaceutically acceptable sequestrating agent.
 9. Amethod as defined in claim 6, which further comprises adding to thecomposition from a trace amount to about 5% by mass of the compositionof a pharmaceutically acceptable anti-oxidant.
 10. A composition asdefined in claim 1, wherein the fraction of the initial thyroid hormoneconcentration in the composition remaining after storage of thecomposition at 25° C. in air for 6 months is at least 0.94.
 11. Acomposition as defined in claim 1, wherein the fraction of the initialthyroid hormone concentration remaining after storage of the compositionat 25° C. under nitrogen for 6 months is at least 0.95.
 12. Acomposition as defined in claim 1, wherein the thyroid hormone isL-3,5,3′,5′-tetraiodothyronine (levothyroxine or LT4) or apharmaceutically acceptable salt thereof.
 13. A composition as definedin claim 1, wherein the thyroid hormone is L-3,5,3′-triiodothyronine(liothyronine or LT3) or a pharmaceutically acceptable salt thereof. 14.A composition as defined in claim 1, wherein the thyroid hormone isL-3,3′,5′-triiodothyronine (LrT3) or a pharmaceutically acceptable saltthereof.
 15. A composition as defined in claim 1, wherein the thyroidhormone is L-3,5-diiodothyronine (LT2) or a pharmaceutically acceptablesalt thereof.
 16. A method as defined claim 6, wherein the thyroidhormone is L-3,5,3′,5′-tetraiodothyronine (levothyroxine or LT4) or apharmaceutically acceptable salt thereof.
 17. A method as defined inclaim 6, wherein the thyroid hormone is L-3,5,3′-triiodothyronine(liothyronine or LT3) or a pharmaceutically acceptable salt thereof. 18.A method as defined in claim 6, wherein the thyroid hormone isL-3,3′,5′-triiodothyronine (LrT3) or a pharmaceutically acceptable saltthereof.
 19. A method as defined in claim 6, wherein the thyroid hormoneis L-3,5-diiodothyronine (LT2) or a pharmaceutically acceptable saltthereof.
 20. A method as defined in claim 5, wherein the mammal is ahuman.